Published online July 1, 2005
PEDIATRICS Vol. 116 No. 1 July 2005, pp. 160-167 (doi:10.1542/peds.2004-2312)
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Safety and Immunogenicity of the American Academy of Pediatrics–Recommended Sequential Pneumococcal Conjugate and Polysaccharide Vaccine Schedule in Pediatric Solid Organ Transplant Recipients

Philana Ling Lin, MD, MSc*, Marian G. Michaels, MD, MPH*,{ddagger}, Michael Green, MD, MPH*,{ddagger}, George V. Mazariegos, MD{ddagger}, Steven A. Webber, MD*, Kathy S. Lawrence, MN*, Kathy Iurlano, RN{ddagger} and David P. Greenberg, MD*

* Department of Pediatrics, Children's Hospital of Pittsburgh
{ddagger} Department of Surgery and Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective. Solid organ transplant recipients are at increased risk for invasive pneumococcal disease. The American Academy of Pediatrics recommends immunization with sequential pneumococcal vaccines for this group; however, data are lacking. Accordingly, this study was designed to evaluate the safety and immunogenicity of the recommended regimen.

Methods. Pediatric solid organ transplant recipients (n = 25) between 2 and 18 years of age who had not previously received 7-valent conjugate pneumococcal vaccine (PCV7) were enrolled. These patients received 2 doses of the PCV7 and a single dose of the 23-valent polysaccharide pneumococcal vaccine (23V). Each vaccine dose was given 2 months apart. Healthy age-matched controls (n = 23) were enrolled for comparison. Controls received a single dose of PCV7 followed 2 months later by a single dose of 23V. Antibody concentrations to serotypes 1, 4, 5, 6B, 9V, 14, 18C, 19F, and 23F were measured by enzyme-linked immunosorbent assay prevaccination, 2 months after each vaccine dose and 5 to 7 months after 23V. Local and systemic reactions to each vaccine dose were recorded.

Results. Systemic and injection-site reactions were comparable between the 2 groups. Significant rises in serotype-specific pneumococcal antibody geometric mean concentrations from prevaccination levels were observed in both groups; however, final antibody responses to serotypes 1, 4, 9V, 14, 18C, 19F, and 23F were significantly lower in solid organ transplant recipients compared with the control group. Antibody concentrations did not increase significantly among solid organ transplant patients after the second dose of PCV7. No additional increase in PCV7-associated serotype-specific antibody levels was observed after the 23V dose in both groups. Heart transplant recipients had lower antibody responses compared with liver transplant recipients.

Conclusions. Although the pneumococcal vaccine regimen was safe and immunogenic among pediatric solid organ transplant recipients, the patients did not seem to benefit from the second dose of PCV7 or from the 23V dose given 2 months later. Additional studies are needed to determine the number of PCV7 doses and the interval between PCV7 and 23V to induce optimal responses.

Key Words: solid organ transplant recipient • invasive pneumococcal disease • conjugate pneumococcal vaccine • vaccine response

Abbreviations: AAP, American Academy of Pediatrics • PCV7, 7-valent conjugate pneumococcal vaccine • 23V, 23-valent polysaccharide pneumococcal vaccine • PTLD, posttransplant lymphoproliferative disease • GMC, geometric mean antibody concentration

Solid organ transplant recipients are at increased risk of bacterial infections including invasive pneumococcal infections.1–4 This has also been shown in pediatric solid organ transplant recipients,5,6 who (like their adult counterparts) require immunosuppressive medications to prevent graft rejection. Children face the additional burden of increased risk of bacterial infections because they may not have developed protective antibodies before transplantation was performed. Moreover, the effects of long-term immunosuppressive agents during critical time points of immune maturation in these children are not well understood. The American Academy of Pediatrics (AAP) recommends that pediatric solid organ transplant recipients receive vaccine for the prevention of invasive pneumococcal disease. Specifically, the AAP recommends that immunocompromised children 2 to 5 years of age who have not been vaccinated previously with 7-valent conjugate pneumococcal vaccine (PCV7) receive 2 doses of the PCV7 followed by a dose of 23-valent polysaccharide pneumococcal vaccine (23V).7 However, limited data exist regarding both the safety and immunogenicity of the sequential vaccine regimen in this vulnerable population. Accordingly, a prospective, nonrandomized, open-labeled study was conducted to evaluate the safety and immunogenicity of the vaccine schedule recommended by the AAP for children who received solid organ transplant. PCV7 and 23V were administered to a group of similar-aged healthy children to generate comparative data.


   METHODS
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 ABSTRACT
 METHODS
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Study Subjects
Pediatric solid organ transplant recipients (ie, heart, double-lung, heart-lung, liver, small bowel, multiple abdominal organs) between 2 and 18 years of age followed at the Children's Hospital of Pittsburgh were enrolled in the study between August 1, 2001, and October 30, 2003. To ensure a period of stable immunosuppression, eligibility was limited to children who were at least 6 months posttransplantation and had not been treated for either allograft rejection or posttransplant lymphoproliferative disease (PTLD) in the previous 6 months. Rejection was defined by histologic criteria and the requirement for inpatient augmentation of immunosuppressive therapy (ie, admission to the hospital for intravenous corticosteroids or anti-T-cell antibody). The diagnosis of PTLD was based on characteristic histologic findings and the consensus of the managing transplant clinicians. A period of 9 months was required before enrollment if treatment of PTLD included the use of rituximab (Rituxan) because of its prolonged effects on B-cell suppression. Children were excluded if they had (1) received blood products (including any pooled immunoglobulin product) within 6 months of enrollment or during study participation, (2) a history of severe reaction to diphtheria toxoid–containing vaccines, (3) known or suspected history of immunodeficiency distinct from therapeutic immunosuppression, and (4) previous history of having received the pneumococcal conjugate vaccine. Children who had received pneumococcal polysaccharide vaccine >3 years before study entry were also eligible for enrollment. Most solid organ transplant recipients received high-dose corticosteroids and tacrolimus as induction immunosuppression and were maintained on tacrolimus with or without additional maintenance immunosuppressive agents (eg, mycophenolate mofetil, sirolimus, prednisone).

Healthy age-matched controls were recruited from the Children's Hospital of Pittsburgh primary care clinic and its satellite facilities. Control children were eligible if they had no significant medical history requiring the use of immunosuppressant medications or receipt of any blood product in the last 6 months. Children were ineligible if they had a history of severe reaction to diphtheria toxoid–containing vaccines, known or suspected immunodeficiency, or received any form of pneumococcal vaccine previously.

Basic demographic data including age, race, gender, and medical history were obtained on both solid organ transplant and control participants at the time of enrollment. A thorough review of immunization records and medical records was also performed. At each study visit, participants were queried about intercurrent use of all medications and nonpneumococcal vaccinations.

To detect a 35% difference in response rates between groups with a power of 80% (1-ß = .80) and type I error rate of 5% ({alpha} = .05), a sample size of 50 solid organ transplant recipients and 25 control participants was necessary. Response was defined arbitrarily as achieving an anticapsular antibody level of >0.15 µg/mL to serotype 4. Because of limited enrollment noted in November, 2002, the sample size was revised to a goal of 33 solid organ transplant participants with an equal number of age-matched controls to achieve the same power and error parameters noted above.

This protocol was approved by the Children's Hospital of Pittsburgh Human Rights Committee.

Vaccine Schedule
Pneumococcal vaccines used in this study were commercial lots of PCV7 and 23V. The PCV7 (Prevnar [Lederle Laboratories, Pearl River, NY]) contains oligosaccharides and polysaccharides in quantities of 2 µg each of serotypes 4, 9V, 14, 18C, 19F, and 23F and 4 µg of serotype 6B. The 23V (Pnu-Immune [Wyeth-Lederle Laboratories, Pearl River, NY] or Pneumovax [Merck and Co, Inc, West Point, PA]) contains polysaccharides in quantities of 25 µg each of serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F. Either form of 23V was considered acceptable to accommodate the practices of the primary care physicians of the participants. In general, children who were residents of western Pennsylvania came to Children's Hospital of Pittsburgh for each vaccine visit with our research staff. Solid organ transplant participants who had already moved away from the Pittsburgh area received vaccines from their local primary care physician.

Pediatric solid organ transplant recipients received 2 doses of PCV7, 6 to 8 weeks apart, followed by a single dose of 23V 6 to 8 weeks after the second PCV7 dose. Control subjects were given a single dose of PCV7, followed 6 to 8 weeks later by a single dose of 23V. Participants were instructed not to receive other immunizations within 2 weeks of the study vaccines.

Serum Antipneumococcal Antibodies
Serologic studies were obtained at baseline, 6 to 8 weeks after each PCV7 dose, and 4 to 8 weeks and 5 to 7 months after 23V in all participants. Serotype-specific pneumococcal antibody concentrations to 1, 4, 5, 6B, 9V, 14, 18C, 19F, and 23F were determined by using enzyme-linked immunosorbent assay after C polysaccharide preabsorption by technicians unaware of the patients' identities. All antibody assays were performed by Moon Nahm (University of Alabama, Birmingham, AL).8 Serum specimens were stored at –80°C before analysis.

Safety Data
At the time of vaccination, medical providers (either a study nurse or health care provider) were asked to record the appearance of local reactions occurring within 30 minutes of injection. At the time of each vaccination visit, parents were given a diary card, thermometer, and measuring tape. On postvaccination days 1 through 3, parents were asked to record the presence or absence of redness and swelling (in millimeters), pain/tenderness (graded none, mild, moderate, or severe), loss of appetite, vomiting, headache, fussiness, increased sleep, or other potential adverse reactions. Parents were telephoned by research staff 4 days after the immunization, and the data from the diary card was recorded. Information regarding changes in medications or medical care and receipt of other nonpneumococcal vaccines was reviewed during each telephone contact and study visit.

Statistical Analysis
Geometric mean antibody concentrations (GMCs) for each pneumococcal serotype were compared between control and solid organ transplant participants by using the 2-tailed, unpaired Student's t test after log transformation of the raw data. Intent-to-treat analysis was performed. Undetectable antibody levels (defined as <0.02 µg/mL) were assigned a value of 0.01 µg/mL for the analysis. Proportional comparisons (eg, safety profiles among controls and solid organ transplant participants) were analyzed by Fisher's exact test. All analyses were conducted by using a 2-sided P value with a type I error rate of ≤.05. Statistical computations were performed by using STATA 8.0 (Stata Corp, College Station, TX).


   RESULTS
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 ABSTRACT
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 RESULTS
DISCUSSION
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Twenty-nine pediatric solid organ transplant recipients were enrolled in the study. Four of the 29 were excluded within 1 month of enrollment, and their data were not subjected to analysis; of these 4 children, 2 were exposed to varicella and required zoster immunoglobulin and 2 were belatedly recognized to have previously received pneumococcal conjugate vaccine. Four other patients were excluded later in the course of the study for the following reasons: varicella exposure and receipt of zoster immunoglobulin; life-threatening graft rejection requiring extracorporeal membrane oxygenation; diagnosis of PTLD; and receipt of 3 doses of PCV7 instead of 2 doses. Data from these latter 4 participants were analyzed up to time of their exclusion. Twenty-one solid organ transplant recipients completed all visits.

Demographic information regarding the solid organ transplant recipients and control participants included in the analysis is depicted in Table 1.


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  		TABLE 1. Demographic Comparison Between Pediatric Solid Organ Transplant (SOT) Recipients and Age-Matched Controls

 
Immunogenicity of Pneumococcal Vaccine Series
Prevaccination and postvaccination serotype-specific GMCs (µg/mL) for both solid organ transplant and control groups are shown in Table 2. Control participants demonstrated a significant increase in GMCs for all serotypes contained in PCV7 after a single dose of PCV7. Likewise, this group had significantly increased GMCs to serotypes 1 and 5 after the 23V. Among the solid organ transplant participants, GMCs of PCV7-associated serotypes increased significantly above prevaccination baseline values after a single dose of PCV7 for all PCV7-associated serotypes except serotype 19F, which did not increase significantly from baseline even after the second dose of PCV7. Among the solid organ transplant recipient group, the GMC to serotype 5 did not increase substantially over baseline after the 23V dose. It is of interest that no additional increase in GMCs of PCV7-associated serotypes was observed in either the control or solid organ transplant groups after the dose of 23V. Postvaccination (4–8 weeks after the 23V dose) GMCs of serotypes 1, 4, 9V, 14, 18C, 19F, and 23F were significantly higher in control patients when compared with their respective solid organ transplant participants (see Table 2). GMCs obtained 5 to 7 months after the 23V were statistically higher than baseline among both solid organ transplant and control groups. Postvaccination serologic fold rises above baseline levels between solid organ transplant and controls are shown in Fig 1.


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  		TABLE 2. Serotype-Specific Pneumococcal Antibody GMCs (µg/mL [95% CI]) Among Pediatric Solid Organ Transplant (SOT) Recipients and Age-Matched Controls Before and After Vaccinations

 

Figure 1
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  		Fig 1. Serologic fold rise in titers (4–8 weeks after 23V dose) from baseline among pediatric solid organ transplant recipients (SOT) and control participants. *P < .05 (significant difference) in fold rise from baseline among solid organ transplant recipients and control participants.

 
The percentage of solid organ transplant and control participants with serotype-specific antibody concentrations ≥0.5 and ≥1.0 µg/mL pre–pneumococcal vaccine and post–pneumococcal vaccine series (PCV7 + 23V) are depicted in Table 3. A significantly lower proportion of solid organ transplant participants achieved antibody concentrations ≥1.0 µg/mL than control participants after the 23V dose for serotypes 1, 4, 9V, and 14.


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  		TABLE 3. Percent of Solid Organ Transplant (SOT) and Control Participants With Serotype-Specific Pneumococcal Antibody Concentrations ≥0.5 µg/mL and ≥1.0 µg/mL* Before and After Vaccination

 
Subgroup Analyses
There were no differences in baseline or postvaccination serotype GMCs by race in the control group (this was not evaluable in the solid organ transplant group). Three of the 25 solid organ transplant participants had previously received the 23V >3 years before enrollment. There were no significant differences in prevaccination or postvaccination antibody concentrations among these 3 solid organ transplant recipients compared with 23V-naive solid organ transplant recipients. Likewise, there were no significant differences in antibody responses among subjects who received Pneumovax (Merck and Co, Inc) compared with those who received Pnu-immune (Wyeth-Lederle Laboratories) for their dose of 23V.

No significant differences were detected in the PCV7-specific antibody responses after the first and second doses of PCV7 among solid organ transplant participants receiving tacrolimus alone compared with those treated with tacrolimus plus other immunosuppressant medications. Heart transplant recipients demonstrated lower pneumococcal antibody responses compared with liver transplant participants for serotypes 1, 5, 6B, 9V, 18C, and 19F (see Table 4). The proportion of heart and liver transplant recipients receiving tacrolimus alone compared with those treated with tacrolimus plus other immunosuppressant medications was not significant. Likewise, age at the time of transplantation did not differ between heart and liver transplant recipients.


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  		TABLE 4. Serotype-Specific Pneumococcal GMCs (µg/mL [95% CI]) Among Heart (HTX) and Liver (LTX) Solid Organ Transplant Participants

 
Safety Data
There were no serious adverse events thought to be caused by the PCV7 or 23V. Ninety-eight percent (117 of 120) of the diary cards were completed for solid organ transplant and control participants. The most frequent adverse reaction was pain and/or tenderness at the injection site. A significantly greater proportion of control subjects reported pain/tenderness (96%) than solid organ transplant patients (80% and 72% after the first and second doses, respectively). Of the solid organ transplant participants, 17% to 21% reported fussiness, headache, and loss of appetite after the 23V, somewhat more than the control subjects. In both groups, the majority of injection-site and systemic reactions were reported as mild to moderate in severity and generally resolved within 2 days after vaccination. No cases of invasive pneumococcal disease were observed among participants during the time of the study.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
It is the general consensus among transplant physicians and infectious disease experts that pediatric solid organ transplant recipients should be brought "up to date" with the standard nonlive vaccines beginning 6 months to 1 year after transplantation.7 However, little data exist regarding immunogenicity and efficacy of these vaccines. Previous investigations have shown that transplant recipients produce low antibody responses to hepatitis B vaccine,9–11 influenza vaccine,12,13 and the pneumococcal polysaccharide vaccine.14–16 The safety and immunogenicity of the AAP-recommended pneumococcal conjugate and polysaccharide vaccine series in pediatric solid organ transplant recipients has not been reported previously.

This study demonstrates that the sequential conjugate and polysaccharide vaccine regimen is generally immunogenic and safe among pediatric solid organ transplant recipients. Overall safety profiles were similar among control and solid organ transplant participants. However, the height of postvaccination antibody responses for serotypes 1, 4, 9V, 14, 18C, 19F, and 23F among solid organ transplant recipients was significantly lower than the age-matched control participants despite the fact that both groups developed serotype-specific GMCs greater than baseline. The exception to this was serotype 19F, for which the postvaccination GMC did not increase significantly above baseline in the solid organ transplant recipients. It should be noted, however, that the baseline level for serotype 19F was 3.09 µg/mL in these children.

The less robust response to vaccination in solid organ transplant recipients is likely attributable, at least in part, to the immunosuppressive regimens used to prevent rejection. The observed differences may be due to the overall net state of immunosuppression or to the specific mechanism of immunosuppression caused by each medication. It has been hypothesized that T cell independent vaccines (eg, polysaccharide vaccines) may be ideal for solid organ transplant recipients12 because many antirejection medications are designed specifically to impair T cell function (the primary immune response associated with cellular rejection). However, many of the current immunosuppression regimens affect both T- and B-cell function.17 The current study showed no difference in antibody responses among solid organ transplant participants prescribed tacrolimus alone compared with those prescribed tacrolimus and other immunosuppressant medications. However, antibody response with regard to degree of immunosuppression could not be evaluated thoroughly because of the limited number of patients receiving various medications and the difficulty in assessing overall immunosuppression.

The specific solid organ transplanted may impact on the risk of invasive pneumococcal disease and the likelihood of developing an immunogenic response to vaccine. Several investigators have reported an increased incidence of invasive pneumococcal disease among pediatric and adult heart transplant1,6 and renal transplant3 recipients. In a large review of invasive pneumococcal disease cases among pediatric solid organ and hematologic transplant patients, 31 cases were observed in solid organ transplant recipients. Of these, heart transplant recipients accounted for the most (n = 15) cases, followed by liver transplant (n = 10), kidney transplant (n = 5), and bowel transplant (n = 1) recipients.5 However, results of this study do not provide the denominator data necessary to determine the overall incidence of invasive pneumococcal disease by organ transplant type.

The current AAP-recommended pneumococcal vaccine regimen for solid organ transplant recipients was based on a limited study of 23 children with sickle cell hemoglobinopathy given either 23V alone or 2 doses of PCV7 (6 to 8 weeks apart) followed by a single dose of 23V 8 weeks later. Children who received the sequential PCV7 and 23V series had higher PCV7-associated GMCs compared with the 23V-only group. Antibody responses to all PCV7-associated serotypes increased significantly after the first dose of PCV7 with the exception of serotype 6B, which increased after the second dose of PCV7.18 Thus, the AAP recommended that 2 doses of PCV7 be given to patients at high risk of invasive pneumococcal infection, including children on immunosuppressive therapy.19 The current study demonstrates significant increases in all PCV7-associated serotype-specific GMCs after the first dose of PCV7 but only moderate (not significant) increases after the second dose of PCV7. The lack of significant antibody increases after a second dose of PCV7 in our pediatric transplant recipients raises questions as to the value of providing this additional vaccine dose.

Only 2 serotypes specific to the 23V were tested in this study. Among the solid organ transplant patients, a significant increase in the GMCs was observed for serotype 1 but not for serotype 5. In contrast to earlier studies, no increase in the GMCs of PCV7-associated serotypes was observed in either control or solid organ transplant groups after a dose of 23V.18,20 O'Brien et al20 observed dramatic increases in PCV7-associated serotypes after 23V among children with sickle cell hemoglobinopathy. The interval between the last dose of PCV7 and 23V was at least 12 months in their study. Thus, to induce a booster response, the interval between PCV7 and 23V may need to be >2 months. Accordingly, pediatric solid organ transplant recipients who have not received PCV7 previously may benefit from a single dose of PCV7 followed by a single dose of 23V given 12 months later. Likewise, children who have received PCV7 previously as part of the universal childhood immunization program might respond better if the 23V is given at least 12 months after the last dose of PCV7. Additional studies should be conducted to evaluate these hypotheses. Although this study did not evaluate vaccine responses of pediatric patients awaiting transplantation, it is likely that their responses would be greater than after transplantation and should be encouraged.

There were a number of limitations to this study. We did not exclude the administration of other vaccinations for the study. Thus, antibody responses to PCV7 may have been affected by priming with diphtheria toxoid or CRM197. However, only 1 subject (a solid organ transplant participant) received any Haemophilus influenzae type b and diphtheria-tetanus-acellular pertussis vaccine during the study. This occurred 17 days before the second dose of PCV7. Thus, we did not feel that this greatly impacted the study results. The primary limitation to this study was the small number of solid organ transplant recipients that were evaluated, which prevented meaningful comparisons between different solid organ transplant types and different immunosuppressive regimens. In addition, only 2 serotypes exclusive to 23V were evaluated. Last, this study focused on immunogenicity rather than efficacy as a primary end point. The exact concentration of serum antibody needed to prevent invasive disease is unknown and may vary for each serotype. In an efficacy study of PCV7 in healthy children, Black et al21 estimated that a GMC of ≥0.5 µg/mL could be considered protective based on their data. However, these data cannot necessarily be extrapolated to older children, solid organ transplant patients, or other immunosuppressed hosts. It is interesting that although the use of PCV7 has been limited among adults at risk for invasive pneumococcal disease, current data do not support its use. Among adult renal transplant patients given a single dose of PCV7, only a trend toward greater pneumococcal quantitative antibody levels was observed compared with those who received 23V. Moreover, functional antibody responses (as measured by opsonophagocytic assay) were no different between groups.22

Data from this study provide a substantial contribution to our understanding of the immune responses elicited by pneumococcal vaccines among pediatric solid organ transplant recipients. Although the sequential pneumococcal vaccine regimen was found to be safe and immunogenic among solid organ transplant recipients, postvaccination antibody responses were lower than age-matched controls. Additional studies are needed to determine the optimal number of PCV7 doses and the interval between PCV7 and 23V to reliably induce a boosting effect.


   ACKNOWLEDGMENTS
 
We thank Lederle Laboratories for donating substantial quantities of the 7-valent pneumococcal conjugate and 23-valent pneumococcal polysaccharide vaccines. This research was supported in part by a grant from the John R. McCune Charitable Trust to the Children's Hospital of Pittsburgh Vaccine Center.

We are indebted to Dr Ellen Wald for critical review of the manuscript.


   FOOTNOTES
 
Accepted Mar 8, 2005.

Address correspondence to Philana Ling Lin, MD, MSc, Division of Allergy, Immunology, and Infectious Diseases, Children's Hospital of Pittsburgh, 3705 Fifth Ave, Pittsburgh, PA 15213. E-mail: philana.lin{at}chp.edu

Dr Greenberg's current affiliation is Aventis Pasteur, Swiftwater, PA.

No conflict of interest declared.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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  8. Wernette CM, Frasch CE, Madore D, et al. Enzyme-linked immunosorbent assay for quantitation of human antibodies to pneumococcal polysaccharides. Clin Diagn Lab Immunol. 2003;10 :514 –519[Free Full Text]
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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics




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